The present invention relates to a process for operating a packaging transport system in which contaminated objects are packed in contaminated packaging which is bacteria-impermeable but gas-permeable, said contaminated objects being then sterilized in this state, the packaging then in this state, after the possible removal of some packaging parts, being sterilized again in a transfer lock on its outer side and being guided into a sterile clean room.
The present invention relates in particular to a process for a contamination-free insertion of already sterilized syringes, possibly having injecting needles, into a filling device surrounded by a clean room for filling and sealing of the syringes, in which sterile transport containers (so-called tubs) containing the syringes are provided with a bacteria-impermeable but gas-permeable cover and are sealed in additionally by a similar bacteria-impermeable but gas-permeable packaging, said tubs being first released from the surrounding packaging and thereafter, while still being provided with the cover, are again sterilized on their outer side and guided into the clean room.
A process of the latter mentioned type, for which no previous publication is known to the applicant, is prior art in practice. The above mentioned transport containers or tubs are plastic tubs into which a perforated tray, frequently called a nest, is set. Ready made syringes, which may be provided with adhering needles or needle caps, hang through the holes of the tray. These ready-made syringes are already sterilized and need only to be filled and sealed with a plunger. The plastic tubs are sealed on their upper side by means of a bacteria-impermeable but gas-permeable foil. This consists, as a rule, of polyester and is known under the trademark Tyvek. A foil of this type comprises pores, which are large enough to allow gas molecules to diffuse through, but which are small enough to prevent microorganisms from penetrating the foil.
The tubs are provided with a bag-like packaging, in which also a bacteria-impermeable, but gas-permeable Tyvek strip is integrated. The re-packed tubs are, as a rule, subsequently sterilized with a highly poisonous gas, ethylene oxide. This gas penetrates during sterilization through the surrounding packaging and also through the cover of the plastic tubs into the interior of the tubs and sterilizes hereby all surfaces within the packaging. The ethylene oxide is drawn off again by means of evacuation, and after several days of further removing of poisonous gas in a special store room, the tubs can be sold. It is also known that the tubs can, as an alternative, be sterilized by means of gamma rays.
In order to fill the syringes and to close them by means of a pump plunger, they must be guided into a filling device. The process of filling objects with sensitive, liquid pharmaceuticals always take place under sterile conditions. The filling devices are either installed accordingly in clean rooms or possess their own small clean room, with stands over the filling devices, a so-called isolator.
The difficulty lies in guiding the syringes into the clean room in an absolutely sterile condition without recontaminating them. Clearly, no microorganisms should be hereby permitted to enter the clean room.
In the case of the known process, the packaging, having been disinfected by means of wiping with an alcohol-soaked cloth, is removed outside of the clean room, for example by means of alcohol-disinfected gloves. Even at this point, there is already the danger that particles containing microorganisms will fall from the packaging onto the tub. After the tub has been subsequently inwardly transferred into the clean room, the bacteria-impermeable Tyvek foil is removed from the tub, for example via contact gloves made of hypalon, so that access is gained to the syringes to be filled. Should, however, the Tyvek foil be recontaminated with particles containing microorganisms, these could fall down and land on the syringes when the foil is removed. In order to prevent this, an additional loose sheet of Tyvek lies over the open syringes, which is manually removed just before the nest is inserted into the filler.
In order to minimize the above mentioned risk, it has been the practice for some time that the tub, relieved of the packaging, but still sealed in by the Tyvek cover, is again sterilized, desirable, however, only on the outer side, so that the already sterilized syringes are in no way impaired. This sterilization of the outer side takes place in a type of lock, in which the tub is sterilized by means of high-energy electronic rays (E beams). This one single applicable post-sterilization process has many disadvantages: it is not only costly and technically very complicated, but protection measures against the E beams are necessary. This requires permission for the erection and operation as well as qualified personnel. In addition, aggressive radicals are set free due to the high-energy ionisating beams, which could reach the inner surface of the syringes and which could react with the product in the syringes after filling. The sterilization of the outer side only has remained impracticable.
It is an object of the present invention to construct a technically far simpler, smaller and cheaper lock, which permits a post-sterilization of the outer side of the packaging, in particular of the tubs after being relieved of their packaging and which omits the application of the extremely health-damaging ionisating beams. It should be hereby ensured that the surfaces of the already sterilized syringes which come into contact with the product to be filled in the syringes, are not contaminated with any radicals or otherwise impaired during post-sterilization.
This object has been achieved in accordance with the present invention in that the renewed sterilization of the outer side of the packaging, in particular the transport containers, takes place in an evacuable sterilization chamber which serves as a lock, whereby a vapour mix of water steam and hydrogen peroxide steam is applied abruptly, by means of pre-evacuation of the sterilization chamber, in the form of a condensation layer on the outer side of the packaging or the transport containers, directly thereafter the condensation layer and the vapour mix which has not condensed are removed from the sterilization chamber by means of further evacuation, so that neither the vapour mix nor the condensation layer gets through the packaging or the cover in unadmissible amounts to reach the objects, or in this case, the syringes.
In the process according to the present invention it is initially provided that the sterilization chamber is pre-evacuated using a pump stand, so that the pressure in the sterilization chamber sinks. As soon as pre-evacuation pressure is reached in the sterilization chamber, a vapour mix of water steam and hydrogen peroxide steam flows abruptly into the sterilization chamber without the aid of any carrier gas flow, but driven solely by the difference in pressure between an evaporating apparatus and the pre-evacuated sterilization chamber. As a result of the expansion of the vapour mix, which now not only fills out the volume of the evaporating apparatus, but also that of the much larger sterilization chamber, the vapour mix cools down. The cooling results in a strong oversaturation of the vapour mix, which is why the vapour mix condensates at the moment of entry onto all accessible surfaces within the sterilization chamber. Because of the evaporation enthalpy which is released during condensation, the forming condensate is for a moment heated to such a degree that hydrogen peroxide is dissociated in large amounts, whereby the microorganisms are abruptly destroyed at the moment of condensation of the vapour mix as it expands into the sterilization chamber, before the vapour mix or the condensate layer can penetrate the cover in any inadmissible way.
The speed of the pre-evacuation must be adapted to the flow resistance of the cover of the transport containers. In one variation of the process according to the present invention, this permits the pressure inside the transport containers to be higher than the pressure in the sterilization chamber, at least initially, so that the vapour mix cannot get through the cover into the inside of the transport containers or even as far as to the syringes. The aim is to prevent the condensate formed on the outer side of the cover from being pressed through the gas-permeable foil and into the tubs. The individual parameters, namely the pressure in the evaporator before the flowing-in, the volume ratio between the evaporator and the sterilization chamber, the pre-evacuation pressure as well as the pressure inside the tubs in the moment of the flowing-in of the vapour mix, must, of course, be in the correct ratios to one another.
As in the process described according to the present invention the microorganisms are destroyed instantly in the moment of condensation formation, the removal of the condensation layer from the sterilization chamber can take place, in many cases without waiting for a longer acting time, directly after the flowing-in of the vapour mix. The surfaces covered with a condensate layer located inside the sterilization chamber can be dried by means of simple evacuation of the sterilization chamber down to a pressure below 10 mb, preferably below 1 mb. Because of the difference in pressure which occurs between the inner pressure inside the tubs and the pressure in the sterilization chamber, the air flow out of the tubs is strengthened, so that, expediently as before, no vapour mix can penetrate through the cover into the tubs.
In another variation of the process according to the present invention, use can be made of the fact that the pores of the cover, in size lying in the sub-pm range, prevent even the smallest condensate drops from penetrating. Thanks to the abrupt formation of the condensate, which begins with drops which grow very rapidly and also join together, a kind of sealing effect takes place by means of the condensate being deposited on the pores, so that, expediently, no steam in any great quantities can penetrate through the pores. Even if the sealing effect by the condensate is not in any way complete, it is however good enough to hinder to a great degree the penetration of hydrogen peroxide in the tub for a time span of a few seconds, or at least to slow it down. The sealing effect is technically applicable for a time span of 2 to 4 seconds from the time of the flow-in of the vapour mix; in the case of a less demanding process, for a time span of up to 14 seconds. In the case of a suitable quality of the cover, almost no hydrogen peroxide penetrates into the tubs, even when the pressure in the sterilization chamber during the formation of condensation is higher than the pressure in the inside of the tubs.
The admissible amount of hydrogen peroxide which may be permitted to penetrate through the cover to the inner surfaces of the syringes or to the surfaces of other objects can be considered, within the framework of the present invention, to be a so-called hydrogen peroxide residue, which, for example, measured against the filling volume of the syringes, may not exceed 1.0 ppm (parts per million) and indeed should lie preferably considerably below 0.5 ppm.
From the point of view of a shortening of the duration of the process, both above mentioned variations can be advantageously combined. For practical purposes the process should be so regulated that the inner pressure of the tubs at the start of the flow-in of the vapour mix is significantly higher than the pressure in the sterilization chamber outside of the tubs, but that subsequently the steam pressure of the sterilization chamber which builds up when the vapour mix flows in, is higher than the inner pressure of the tubs, without damaging the condensate for reasons of the sealing effect described above.
A further advantageous embodiment is arrived at when the actual process of subsequent sterilization, namely the depositing of a condensate layer and the subsequent removal of same is repeated at least once. It can hereby in particular be provided that between the end of the removal of the condensate layer of the first sterilization process and the beginning of the depositing of a condensate layer of the subsequent sterilization process the points of support of the tubs on their base is completely changed or displaced, so that any possible areas of the tubs which were covered by the base during the first sterilization process now lie exposed during the second sterilization process. This guarantees that the entire outer-lying surface of the tubs is completely covered at least once by a condensate layer and thus sterilized.
Insofar as the actual process of repeated sterilization is carried out, it is in principal sufficient when the removal of the condensate layer in the previous sterilization process by means of evacuation of the sterilization chamber takes place at a pressure level which lies below the steam pressure of the water at the given temperature of the sterilization chamber, for example up to 70 mb in the case of an exemplary temperature in the sterilization chamber of 40° C. In order to reduce the amount of any hydrogen peroxide which may have penetrated into the tubs, it is however more advantageous to evacuate at below the steam pressure of the applied watery hydrogen peroxide solution at the given temperature in the sterilization chamber, in the case of the named example that is—at a given concentration of the flowing-in vapour mix of 50 percent in weight—at below 42 mb. Even more advantageous, however, is the evacuation of the sterilization chamber under the steam pressure of pure hydrogen peroxide at a given temperature in the sterilization chamber; at a temperature of 40° C. of the sterilization chamber thus below 7 mb.
Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings.